Concentrations of androgens in human benign prostatic hypertrophic tissues incubated for up to three days

Nj, Bolton; Lukkarinen, O; Vihko, R.

doi:10.1002/pros.2990090206

Cited by 14 publications

(7 citation statements)

References 17 publications

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“…Walsh et al (1983) have challenged this concept and have shown that when normal prostate tissue was obtained from patients undergoing cystectomy for bladder cancer, there was no significant difference between the DHT levels in normal and BPH tissue. Several other studies have also noted an increase in the DHT content of BPH tissue when compared to normal prostate (Belis, 1980;Bolton et al, 1986). An increase in the 5areductase activity in BPH tissue when compared to normal prostate has also been reported (Tunn et al, 1988).…”

Section: Dht Hypothesismentioning

confidence: 78%

Androgen, estrogen, and progesterone receptors in normal and aging prostates

Ganesan

Campbell

Bashirelahi

1995

Microscopy Res & Technique

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Testicular hormones regulate the growth and development of the prostate. The presence of androgen receptors in prostatic tissue and their importance in the normal development of the prostate has been established. Age-related changes in the hormonal milieu, and perhaps steroid hormone receptor profile, could set in motion pathological changes leading to the onset of benign prostatic hyperplasia (BPH) or prostate cancer which primarily affect older men. The accumulation of dihydrotestosterone with age, the reawakening of the inductive potential of the prostatic stroma, the altered rate of apoptosis with age, and the age-related changes in the ratio of testosterone:estrogen have all been implicated in the etiology of BPH. In addition to androgen receptors, several studies have documented the presence of estrogen and progesterone receptors in BPH and prostate cancer. So far, most studies have focussed on the correlation between the presence/absence of steroid hormone receptors and response to hormonal therapy. The molecular mechanisms by which these steroid hormone receptors regulate the onset or progression of BPH and prostate cancer are not yet clear. The chronological changes in the levels and distribution of steroid hormone receptors in normal prostatic tissue and the effect of such changes on the synthesis of growth factors, growth factor receptors, and oncogenes should be investigated.

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Section: Dht Hypothesismentioning

confidence: 78%

Androgen, estrogen, and progesterone receptors in normal and aging prostates

Ganesan

Campbell

Bashirelahi

1995

Microscopy Res & Technique

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“…Although it was originally thought that the concentration of dihydrotestosterone in benign prostatic hyperplasia [4.0-13.0 ng/g tissue (32)(33)(34)(35)(36)] was significantly higher than that (1.3-2.1 ng/g tissue) in normal prostate (32,34), a more recent view is that the dihydrotestosterone concentration is the same in normal and hyperplastic tissue when the samples are obtained under physiological conditions (37)(38)(39). Our finding of lower dihydrotestosterone concentrations in prostates from organ donors than in tissue from prostatectomy patients is in agree- on the retention of dihydrotestosterone by stroma is supported, in addition, by the similar stromal dihydrotestosterone concentrations in benign prostatic hyperplasia and carcinoma, notwithstanding a 4-fold difference in stromal 5«-reductase V max values between the two types of tissue.…”

Section: Discussionmentioning

confidence: 98%

Kinetic Parameters of 5α-Reductase Activity in Stroma and Epithelium of Normal, Hyperplastic, and Carcinomatous Human Prostates*

Bruchovsky

Rennie

Batzold

et al. 1988

The Journal of Clinical Endocrinology & Metabolism

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To study the influence of 5 alpha-reductase on the concentration of dihydrotestosterone in prostatic tissue, we measured the activity of this enzyme in stroma and epithelium from 15 normal, 50 hyperplastic, and 20 carcinomatous prostates. Maximum velocity (Vmax) and Km parameters based on the Lineweaver-Burk and Eadie-Hofstee transformations of the Michaelis-Menten equation were related to the stromal and epithelial concentrations of dihydrotestosterone. On the basis of relative Vmax values, there was 6-15 times more 5 alpha-reductase activity in stroma than in epithelium regardless of the histology of the prostate. Stromal enzyme activity also was unique in having a 2- to 5-fold larger mean Km value and greater resistance to competitive and noncompetitive inhibition. Despite the enrichment of 5 alpha-reductase activity in stroma, the dihydrotestosterone concentrations in the stromal and epithelial fractions were very similar. In addition, similar concentrations were found in the stromal fractions of hyperplastic and carcinomatous tissues, notwithstanding a 4-fold difference in the mean Vmax values. This anomaly occurred in association with a large disparity in mean Km values, i.e. 68.3 +/- 1.6 (+/- SE) nmol/L in hyperplasia vs. 23.0 +/- 2.9 nmol/L in carcinoma. The dissociation between parameters of 5 alpha-reductase activity and tissue dihydrotestosterone concentrations was apparent to some extent in benign prostatic hyperplasia, in which the lowest stromal androgen concentrations were found in prostates with the largest Vmax and Km values; also, a rise in stromal Km was almost invariably associated with a proportional increase in Vmax (correlation coefficient = 0.95). These data strongly suggest that the stromal and epithelial forms of 5 alpha-reductase are separate isoenzymes, and that the excess of 5 alpha-reductase in stroma does not promote accumulation of an abnormal amount of dihydrotestosterone. They also imply that both the augmentation of 5 alpha-reductase activity in hyperplastic stroma and the condition of benign hyperplasia of the prostate are mutual consequences of a primary increase in Km.

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“…These findings are consistent with our measurements of f9-fold decrease and f2.5-fold increase in SRD5A2 and SRD5A1 expression, respectively, in the tumor metastases. Alternatively, the concentrations of DHT detected in the tumor metastases we analyzed may actually be an underestimate of the in vivo tumor androgen levels, as several studies have shown that DHT levels in autopsy samples may be factitiously low due to ongoing postmortem androgen metabolism or degradation (40,41). We cannot exclude this possibility, which may also underlie the relatively higher levels of DHT observed in the prostate cancer xenografts, as these tissues can be immediately frozen upon harvesting.…”

Section: Intratumoral Androgens In Metastatic Prostate Cancermentioning

confidence: 91%

Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

et al. 2008

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Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment. [Cancer Res 2008;68(11):4447-54]

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Concentrations of androgens in human benign prostatic hypertrophic tissues incubated for up to three days

Cited by 14 publications

References 17 publications

Androgen, estrogen, and progesterone receptors in normal and aging prostates

Androgen, estrogen, and progesterone receptors in normal and aging prostates

Kinetic Parameters of 5α-Reductase Activity in Stroma and Epithelium of Normal, Hyperplastic, and Carcinomatous Human Prostates*

Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

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